Association between COVID‐19 and consistent mask wearing during contact with others outside the household—A nested case–control analysis, November 2020–October 2021

Abstract Background Face masks have been recommended to reduce SARS‐CoV‐2 transmission. However, evidence of the individual benefit of face masks remains limited, including by vaccination status. Methods As part of the COVID‐19 Community Research Partnership cohort study, we performed a nested case–control analysis to assess the association between self‐reported consistent mask use during contact with others outside the household and subsequent odds of symptomatic SARS‐CoV‐2 infection (COVID‐19) during November 2020–October 2021. Using conditional logistic regression, we compared 359 case‐participants to 3544 control‐participants who were matched by date, adjusting for enrollment site, age group, sex, race/ethnicity, urban/rural county classification, and healthcare worker occupation. Results COVID‐19 was associated with not consistently wearing a mask (adjusted odds ratio [aOR] 1.49; 95% confidence interval [CI] [1.14, 1.95]). Compared with persons ≥14 days after mRNA vaccination who also reported always wearing a mask, COVID‐19 was associated with being unvaccinated (aOR 5.94; 95% CI [3.04, 11.62]), not wearing a mask (aOR 1.62; 95% CI [1.07, 2.47]), or both unvaccinated and not wearing a mask (aOR 9.07; 95% CI [4.81, 17.09]). Conclusions Our findings indicate that consistent mask wearing can complement vaccination to reduce the risk of COVID‐19.


Conclusions:
Our findings indicate that consistent mask wearing can complement vaccination to reduce the risk of COVID-19. pandemic. [1][2][3][4][5] Although COVID-19 vaccines are effective in preventing severe disease, 6,7 individual protection against infection wanes over time and is lower against new Omicron variants. 6 Face masks are a valuable tool in reducing the risk of exposure to SARS-CoV-2 both by blocking emission of respiratory particles from a person with COVID- 19 and by providing individual protection to the wearer against exposure from others. 5,[8][9][10] Evidence for the benefit of face masks includes ecologic analyses of the impact of mask policies at national, 11 state, 12 and county levels, 13 in schools, [14][15][16] estimates of cost-saving, 9,17 models estimating the effect of masks in attenuating SARS-CoV-2 reproductive number, 8,18,19 and a cluster randomized trial of a community-based intervention. 20 Several observational studies have also indicated an individual benefit in protecting the wearer. 1,3,[21][22][23] However, these studies have generally used retrospective questions concerning previous behavior, and there is limited information on the combined benefit of masks and vaccination.
Using real-world data from the COVID-19 Community Research Partnership (CRP), a multi-site, prospective cohort study, we assessed the association between self-reported consistent mask use when interacting with others outside the household and the odds of COVID-19 during November 2020-October 2021. We assessed whether the magnitude of this effect differed by whether participants reported a known contact with a person with SARS-CoV-2 and by participant vaccination status. Lastly, we assessed how mask-wearing behavior changed before and after a self-reported infection as well as the proportion of individuals who reported they had SARS-CoV-2 exposure prior to testing positive.

| Study participants
Participants were enrolled in the COVID-19 CRP, a multi-site prospective cohort study based in the mid-Atlantic and southern United States. 24 Adults affiliated with 10 participating healthcare systems were invited to enroll in the study beginning in April 2020, including patients within health systems; some other community members also enrolled in the study after local advertising via the healthcare system website. Participants completed a daily electronic survey and gave permission to access their electronic health record (EHR) data. A subgroup of adult participants aged ≥18 years were invited to provide monthly dried blood spot (DBS) specimens for serology testing at the following six healthcare systems: Atrium

| Data collection
Study data were collected and maintained via a secure, HIPAA-compliant, online platform, and all participants provided informed consent.
The study was reviewed and approved by the Wake Forest Institutional Review Board (IRB), which served as the central IRB for this study (see 45  "other" if only one dose or an alternative product was received, or if vaccination status was undetermined (e.g., conflicting or inadequate information provided for categorization). We defined "vaccinated" based on receipt of mRNA vaccines for analysis purposes because these vaccines had higher estimated effectiveness during the study period 25 and because <5% of participants within our study population received non-mRNA COVID-19 vaccine products. Participants were considered to be unvaccinated if they reported no vaccination before the index date and if there was no evidence of receipt of a COVID-19 vaccine from any of the three available sources.
Serology was evaluated using DBS specimens collected at home by finger prick on a monthly basis using Whatman 5-spot DBS cards.
All viable specimens were evaluated for anti-spike antibody using a EUROIMMUN qualitative assay for SARS-CoV-2 anti-spike immunoglobulin G (IgG); any DBS card with a positive result underwent reflex testing of a different DBS on the same card for anti-nucleocapsid antibody using a qualitative Roche pan-Ig assay. 26 Both serologic assays used were internally validated for use with DBS cards; evaluation of DBS using the EUROIMMUN assay is reported elsewhere. 27,28

| Analysis design
To compare characteristics and behaviors associated with SARS-CoV-2 infection, we performed a nested case-control analysis within the study cohort. We opted for a nested case-control approach to limit potential biases from differences in the risk of infection over time, different follow-up periods by infection status, variable survey completion, and differences in completion of serology tests. By conditioning on the availability of serology results, this approach was also designed to limit potential selection bias related to the use and return of serology kits by study participants. 29 Participants were eligible for inclusion in the analysis if all the following criteria were met: (1) age ≥ 18 years; (2) returned at least two serology test kits; (3) the first SARS-CoV-2 serology result was negative for anti-spike antibody (indicating no evidence of infection or vaccination) or positive for anti-spike antibody but negative for anti-  Figure S1). For analytic purposes, we considered the estimated date of SARS-CoV-2 infection for caseparticipants to be the symptom onset date.
To account for differences in the risk of infection over the 12-month study period, we matched each case-participant with up to 10 control-participants who had an eligible survey entry on the same date as the case-participant's date of symptom onset. Controlparticipants were eligible if they had no evidence of having a SARS-CoV-2 infection (never self-reported a positive test, no serologic evidence of SARS-CoV-2 infection, no EHR diagnosis, and no positive lab result in EHR). Additionally, control-participants were eligible to be matched on a particular date if they had a survey entry on that date that was followed by a negative serology result in the subsequent 30-90 days, and if there was ≥1 other survey entry during the previous 10 days. We used an optimal matching algorithm, without replacement, maximizing the number of case-participants included. 30 We defined consistent mask use as responding "yes" to the question, "In the last 24 hours, have you worn a face mask or face covering every time you interacted with others (not in your household) within a distance of less than 6 feet?". We included consistent mask use as an exposure variable if reported during the 10 days before the match date (index date); as a secondary analysis, we also reported consistent mask use during the 10 days after the index date (Box S1).
We defined known a COVID-19 exposure as a participant responding "yes" to the question, "Did you have close contact with someone who has tested positive for COVID-19 infection?", during the 10 days before the index date. We determined the likely timing of the reported contact according to the date of the report and how long ago the known exposure was reported to have occurred (last 24 h, last 7 days, 1-2 weeks ago, or >2 weeks ago) (Box S1). For participants who did not self-identify as healthcare workers and who reported a known close contact with a person with COVID-19, participants were asked whether the proximity was <6 feet, and whether the duration of exposure was ≥15 minutes.

| Statistical analysis
After summarizing mask use over time among case-and control-participants, we used conditional logistic regression to compare characteristics of case-and control-participants while accounting for matching by date. In multivariable models comparing characteristics among case-and control-participants, we adjusted for all other characteristics of interest. In multivariable models of consistent mask use or known COVID-19 contact, we adjusted for characteristics that either differed between case-and control-participants or were hypothesized to lead to differential risk of SARS-CoV-2 infection: enrollment site, age group, sex, race/ethnicity, healthcare worker occupation, rurality of county (rural, suburban, or urban), and vaccination status on the index date. We used conditional logistic regression models with interaction terms to assess whether odds ratios (OR) for consistent mask use varied by reported COVID-19 exposure, vaccination status, or healthcare worker occupation. We subsequently stratified analyses by these groups and estimated odds of SARS-CoV-2 infection. Because of sparse data, we used unconditional logistic regression to assess the associations between COVID-19 and the proximity and duration of known COVID-19 exposure among nonhealthcare workers, we used unconditional logistiadjusted by 3-month quarter of index date, age group, sex, race/ethnicity, county classification, and vaccination status.
In addition, we repeated the main analyses evaluating the association between known exposure with COVID-19 and consistent mask use, restricted to participants who were not healthcare workers. To address robustness of our findings under an alternative case definition, we performed a sensitivity analysis of the main estimates limited to case-participants who also had serologic evidence of new SARS-

| Study participants
Among 23,095 participants who were allocated serology test kits, 15,697 (68.0%) had at least two serology test results. After applying exclusion criteria, 359 case-participants were matched to 3,544 control-participants ( Figure 1). The median number of controls per case was 10 (range 2-10).
Compared with control-participants, in an adjusted model, case-participants were more likely to be younger, reside in a county classified as rural, and less likely to have received a second mRNA vaccine dose ≥14 days earlier (Table 1). There were no differences in case-compared with control-participants by sex, healthcare worker occupation, or presence of an underlying health condition. In a multivariable model, symptomatic SARS-CoV-2 infection was associated with younger age, living in a rural or suburban county, health system, and being unvaccinated (Table 1).
F I G U R E 1 Participants included in the analysis. CLI, COVID-19-like illness; EHR, electronic health record. a Of the 30,372 participants enrolled in the CDC study, 28,026 participants did not report participating in a vaccine clinical trial nor self-report a previous COVID-19 diagnosis at the time of enrollment. Of these, 23,095 were allocated at least one serology test kit. b See Table S2 for comparison of participants. c Defined as negative anti-S, or positive anti-S and negative anti-N. d Self-reported through daily survey or EHR diagnosis or lab results. e See Figure S1. f Defined as any symptom in daily survey not reported during the previous 7 days (see Table S3). g Defined as daily survey entry with ≥1 other entry during previous 10 days and ≥1 negative serology result during the next 30-90 days. h Matched on date of survey (1 case to up to 10 controls) T A B L E 1 Overall characteristics of case-participants and control-participants

| Association between reported exposure and COVID-19
The daily survey response rate in the 10 days preceding the index date was similar for case-participants (82%) and control-participants (81%). Among case-participants, 40% (143/359) reported a known exposure to a person with COVID-19 during this period compared with 4% (142/3544) of control-participants ( Table 2). The proportion of case-participants reporting a known exposure began to increase 5 days preceding symptom onset and was highest in the day preceding and the first few days following new symptom onset ( Figure 2B).

| Association between reported mask wearing and COVID-19
During the 10 days preceding the index date, 59% (211/359) of case-participants and 50% (1780/3544) of control-participants reported not wearing a mask during one or more interactions with others outside the household (

| Additional analyses
To assess representativeness within the study cohort, we compared characteristics of participants by whether they had at least two serology test results and were therefore potentially eligible. Overall characteristics of participants were similar by whether serology results were available. However, those with at least two serology test results were more likely to be non-Hispanic White, compared with other participants (Table S2). Additional analyses to address potential limitations in reliance on self-reported positive tests are summarized in Tables S3   and S4. Because participants were only asked to report a new test result since the most recent survey entry and were not directly asked about the collection date, a gap since the most recent survey could lead to an incorrect test date. However, >95% of case-participants had a previous survey entry within the previous 2 days (Table S3). To address potential reliance on participants' report of a positive test, we performed a sensitivity analysis limited to case-participants who also  (Table S4).

| DISCUSSION
In this prospective nested case-control analysis, not consistently wearing a mask during contact with others outside the household was associated with approximately 49% higher odds of COVID-19 during November 2020-October 2021. We found that this association was similar whether or not there was reported close contact with a person with COVID-19, and whether or not the participant was a healthcare worker. On its own, not consistently wearing a mask was also associated with COVID-19 whether or not participants were vaccinated.
Combined with vaccination status, a lack of consistent mask wearing was associated with a stepped increase in the odds of COVID-19participants who did not consistently wear a mask while unvaccinated had the highest odds of COVID-19, whereas those consistently wearing a mask while vaccinated had the lowest odds of COVID-19.
Overall, our findings are comparable with evidence from previous studies indicating that individual mask wearing is associated with decreased odds of infection. 3,10 However, few studies have used prospectively collected data 31,32 or evaluated mask use since the introduction of COVID-19 vaccines or more recent variants. 1,33 Our finding of similar associations between not wearing a mask and COVID-19 whether or not participants were vaccinated is consistent with findings from a case-control study conducted during 2021. 33 Consistent with that study, we found that although the association between mask use and COVID-19 was weaker among vaccinated participants, the modeled association did not differ significantly by vaccination status.
We found a clearer association between not consistently wearing a mask and COVID-19 among vaccinated persons in a sensitivity analysis restricted to case-participants with serologic evidence of infection. This might reflect masks providing additional protection against a subgroup of infections that elicit a more robust systemic immune response or that lead to more illness, because seroconversion is generally associated with more severe disease. 34,35 Although the study data were collected before predominance of the Omicron variant, we found evidence for the benefit of masks whether or not vaccineinduced protection was present-completion of an mRNA primary series was highly protective against infection during the study period. 6,7 Our estimate of an approximately sixfold increased odds of COVID-19 among unvaccinated participants is consistent with a previous analysis during the Delta-predominant period. 36 A majority of case-participants were not able to identify known close contact with a person with COVID-19, and we did not find a sig- Lack of consistent mask use during the 6-10 days and during 1-5 days before symptom onset was associated with infection, suggesting that infection did not result from sudden changes in mask wearing.
However, there was an abrupt decrease in contact with others without a mask following symptom onset, consistent with recommended precautions after SARS-CoV-2 infection. 41 If COVID-19 is confirmed, wearing a high-quality mask is recommended during the 10 days after symptom onset when indoors around others at home and in public. 42 We did not assess the benefit in protecting others by wearing a mask, but previous studies support this benefit, particularly when others are also wearing a mask. 5 Although participants rapidly adopted mask use on the day of symptom onset, pre-existing mask use would likely provide additional protection to others because transmission frequently occurs before symptoms develop. 43  we were unable to distinguish whether the encounter with that infected contact was without a mask, or whether the person with COVID-19 was a household member. We only assessed the individual risk of infection related to not wearing a mask and did not assess additional effects on transmission in the community. We were also unable to assess whether consistent mask wearing was associated with any other protective measures, although among cases there was no difference in reporting a known exposure between those who consistently reported wearing a mask and those who did not ( Figure S2). Our assessment of attributes of known exposures was also limited to exposures that the participant considered to be "close contact." Lastly, the generalizability of our findings might be limited because of geographic focus on east and southern regions of the United States, dependence on access to care for enrollment, overrepresentation of White non-Hispanic and female participants, and by data collection before predominance of the Omicron variant.
Overall, we found that consistently wearing a mask when interacting with others outside the household was associated with lower odds of reported COVID-19. Although the association between consistent mask use and COVID-19 was similar regardless of vaccination status, vaccinated participants who reported consistent mask wearing had the lowest odds of infection, supporting a layered approach to prevention. When local community transmission is high, the Centers for Disease Control and Prevention recommend the use of well-fitting masks or respirators indoors in public to limit the risk of exposure. 49 Mask wearing to minimize the risk of exposure and vaccination to decrease susceptibility if exposed remain complementary strategies to reduce ongoing transmission of SARS-CoV-2.

ACKNOWLEDGMENTS
The COVID-19 Community Research Partnership gratefully acknowledges the commitment and dedication of the study participants. Programmatic, laboratory, and technical support was provided by Vysnova Partners, Inc., Javara, Inc., and Oracle Corporation.

CONFLICTS OF INTEREST
The authors declare that they have no competing interests.

ETHICS APPROVAL
The study was reviewed and approved by the Wake Forest Institu- writing-review and editing.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13080.

DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.